1. Field of Invention
This invention relates to disubstituted polycyclic compounds, pharmaceutical compositions, processes for preparation, and methods of use in mammals to treat cognitive disorders and/or neurological dysfunction and/or mood disturbances such as, but not limited to degenerative nervous system diseases. Additionally, these compounds can be used as reagents in studies on the biochemical mechanism of neurotransmitter based diseases.
2. Background Including Prior Art
Increasingly there is a need for effective treatments for nervous system disorders and neurological deficiencies. Many of these diseases correlate with increasing age, due mainly to degenerative changes in the nervous systems. Although in early stages of some diseases certain systems are rather specifically affected (e.g. cholinergic systems in Alzheimer's Disease and Myasthenia Gravis, the dopaminergic system in Parkinson's Disease, etc.), multiple neurotransmitter system deficiencies (acetylcholine, dopamine, norepinephrine, serotonin) is generally found at later stages of disease such as senile dementia, multi-infarct dementia, Huntington's Disease, mental retardation, etc. This explains the generally observed multiple symptomatology that includes cognitive, neurological, and effective/psychotic components (see Gottfries, Psychopharmacol, 1985, 86, 245). Deficits in the synthesis and release of acetylcholine in the brain are generally thought to be related to cognitive impairment (see Francis, et al., New England J. Med., 1985, 7, 313) whereas neurological deficits (e.g. Parkinsonian symptoms) and mood/mental changes may be related to impairment of dopaminergic and serotonergic systems, respectively. Other neurological deficits (e.g. Myasthenia Gravis) are related to cholinergic deficiencies in the peripheral nervous system.
Treatment strategies employed previously encompass vasoactive drugs like vincamine and pentoxifylline; metabolic enhancers like ergoloid mesylates, piracetam, and naftidrofuryl; neurotransmitter precursors like 1-DOPA, choline, and 5-hydroxytryptamine; transmitter metabolizing enzyme inhibitors such as physostigmine; and neuropeptides like adrenocorticotropic hormone and vasopressin-related peptides. Except for 1-DOPA treatment for Parkinson's Disease and cholinesterase inhibitor treatment for Myasthenia Gravis, these treatment strategies have generally failed to enhance the residual function of the affected systems by enhancing the stimulus-induced release of neurotransmitters. Theoretically, such an enhancement would improve the signal-to noise ratio during chemical transmission of information, thereby reducing deficits in processes related to cognition, neurological function, and mood regulation.
The most pertinent literature citations and patent references related to this invention can be found in DeNoble, et al., Pharmacol. Biochem. Behavior, 1990, 36, 957; Cook, et al., 1990, 19, 301; Nickolson, et al., 1990, 19, 285; and Myers and Nickolson U.S. Pat. No. 4,760,083 (1988), and the references therein. These references describe and teach that a,a-disubstituted aromatic or heteroaromatic of the formula: ##STR2## or a salt thereof wherein X and Y are taken together to form a saturated or unsaturated carbocyclic or heterocyclic first ring and the shown carbon in said ring is a to
at least one additional aromatic ring or heteroaromatic ring fused to the first ring; PA1 one of Het.sup.1 or Het.sup.2 is 2, 3 or 4-pyridyl; or 2, 4 or 5-pyrimidinyl, and the other is selected from PA1 are useful as cognition enhancers. PA1 X and Y=H, halo, lower alkyl, lower alkoxy, NO.sub.2, NH.sub.2, or CF.sub.3 ; PA1 m and n=1-3; PA1 lower=1-6 carbon PA1 R.sup.3 is H, alkyl of 1-6 carbons, halogen, CN, OR.sup.7, N(R.sup.7 R.sup.8), S(O)pR.sup.7, NO.sub.2, or CF.sub.3 ; PA1 R.sup.4 is CO.sub.2 R.sup.7, CON(R.sup.7 R.sup.8), CN, OR.sup.7, N(R.sup.7 R.sup.8), S(O)pR.sup.7, F, Cl, Br, NO.sub.2, or COR.sup.7 ; PA1 R.sup.5 is CO.sub.2 R.sup.7, CON(R.sup.7 R.sup.8), CN, OR.sup.7, N(R.sup.7 R.sup.8), S(O)pR.sup.7, F, Cl, Br, NO.sub.2, COR.sup.7, or CF.sub.3 ; PA1 R.sup.6 is H, alkyl of 1-4 carbons, phenyl, or benzyl; PA1 R.sup.7 and R.sup.8 independently are H, or alkyl of 1-6 carbons; PA1 W is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, tetrahydrofuranyl, thienyl, or phenyl optionally substituted with 0-2 R.sup.5 ; PA1 m is 1 to 4; PA1 n is 1 to 6; and PA1 p is 0 to 2; PA1 A is ##STR8## R.sup.1 is (CH.sub.2)m-W or (CH.sub.2)n-R.sup.4 ; R.sup.2 is alkyl of 1-7 carbons, benzyl substituted with 0-3 R.sup.4, or phenyl substituted with 0-3 R.sup.5 ; PA1 R.sup.3 is H, alkyl of 1-4 carbons, halogen, CN, OR.sup.7, N(R.sup.7 R.sup.8), S(O)pR.sup.7, NO.sub.2, or CF.sub.3 ; PA1 R.sup.4 is CO.sub.2 R.sup.7, CON(R.sup.7 R.sup.8), CN, S(O)pR.sup.7, or COR.sup.7 ; PA1 R.sup.5 is CO.sub.2 R.sup.7, CON(R.sup.7 R.sup.8), CN, OR.sup.7, N(R.sup.7 R.sup.8), S(O)pR.sup.7, F, Cl, Br, NO.sub.2, COR.sup.7, or CF.sub.3 ; PA1 R.sup.6 is H, alkyl of 1-4 carbons, phenyl, or benzyl; PA1 R.sup.7 and R.sup.8 independently are H, or alkyl of 1-6 carbons; PA1 W is pyridyl, pyrimidinyl, tetrahydrofuranyl; PA1 m is 1 to 4; PA1 n is 1 to 6; and PA1 p is 1 or 2. PA1 a. 1,3-Dihydro-1-phenyl-3,3-bis(4-pyridinylmethyl)-H-pyrrolo[2,3-b]pyridin-2- one Dihydrochloride, PA1 b. 1,3-Dihydro-1-(4-chlorophenyl)-3,3-bis(4-pyridinylmethyl)-2H-pyrrolo[2,3-b ]pyridin-2-one Dihydrochloride, PA1 c. 1,3-Dihydro-1-(4-chlorophenyl)-3-(3-cyanophenyl)-3-(4-pyridinylmethyl)-2H- pyrrolo[2,3-b]pyridin-2-one Dihydrochloride, PA1 d. 1,3-Dihydro-1-(4-chlorophenyl)-3-(3-pyridinylmethyl)-3-(4-pyridinylmethyl) -2H-pyrrolo[2,3-b]pyridin-2-one Dihydrochloride, PA1 e. 1,3-Dihydro-1-(4-chlorophenyl)-3-(phenylmethyl)-3-(4-pyridinylmethyl)-2H-p yrrolo[2,3-b]pyridin-2-one, PA1 a. Marfat, et al., Tetrahedron Lett., 1987, 8(35); 4027-4030 PA1 b. R. P. Robinson and K. M. Donahue, J. Org. Chem., 1991, 56, 4805-4806 PA1 c. Ting, et al., J. Med. Chem., 1990, 33, 2697-2706; PA1 d. Stingach, et al., Chemistry of Heterocyclic Compounds, 1981, 1, 54-56 PA1 e. Royer, et al., Tetrahedron, 1980, 36, 2499-2465 PA1 f. Schafer and Gewald, Monatsh. Chem., 1989, 120(4), 315-322 PA1 g. Wolfe, et al., J. Am. Chem. Soc., 1980, 102(10), 3646-3647 PA1 h. By using a combination of the method described by Taylor, et al., Tetrahedron, 1987, 43(21), 5145-5158, "Intramolecular Diels-Alder Reactions of 1,2,4-Triazines. A General Synthesis of Furo [2,3-b]-Dihydrppyrano[2,3-b]Pyridines, and Pyrrol[2,3]Pyridines", and the method described by Stingach, et al., Khimiya Geterotsiklicheskikh Soedinenii, 1981, 1, 54-56, "Thiosemicarbozones of 7-Azaisatin Derivatives" or the method described by Robinson and Donahue, J. Org. Chem., 1991, 56, 4805-4806, "Synthesis of 5-Azaoxindole", the desired starting materials could be made. PA1 i. Fortunak, U.S. Pat. No. 4997954, 05 Mar 1992 PA1 j. Ting, et at., in EP 0347698 Al, and references therein. PA1 k. Beugelmans and Roussi, Chem. Commun., 1979, 950 PA1 l. Goehring, Wolfe, et al., J. Am. Chem. Soc., 1985, 107, 435 PA1 m. Clark, et al., Synthesis (1991), 10, 871-878.
(a) 2, 3 or 4-pyridyl PA2 (b) 2, 4 or 5-pyrimidinyl PA2 (c) 2-pyrazinyl PA2 (d) 3 or 4-pyridazinyl, PA2 (e) 3 or 4-pyrazolyl, PA2 (f) 2 or 3-tetrahydrofuranyl, and PA2 (g) 3-thienyl
Patent WO 91/01/306, Feb. 7, 1991 discloses oxoindole derivatives of formula: ##STR3## useful for treating senile dementia, i.e. improving brain functions and activating and protecting brain metabolism. In the above formula, R.sup.1 represents hydrogen, halogen lower alkyl, or lower alkoxy; R.sup.2 represents hydrogen or lower alkyl; R.sup.3 represents --CH.sub.2 -- R.sup.5, wherein R.sup.5 represents alkyl which maybe cyclic, benzodioxanyl, or phenyl which may be substituted with a plurality of hydrogen, lower alkyl, lower alkoxy, hydroxy, diethylamino, trifluromethyl, nitrile, nitro, or benzyloxy; alternatively R.sup.2 and R.sup.3 may be combined together to form .dbd.CH--R.sup.5, wherein R.sup.5 is defined above; and R.sup.4 represents 1-propylbutyl, pyridyl, or phenyl or substituted phenyl.
EP 415102-A discloses a series of 1,3-dihydro-1-(pyridinylamino)-2H-indol-2-ones as having analgesic, anticonvulsant, and/or memory enhancing activity and are useful in the treatment of Alzheimer's disease. ##STR4## where R.sup.1 -R.sup.3 =H, lower alkyl (opt. substd. by aryl); methyl or ethyl substituted by pyridyl of thienyl; or aryl; or R.sup.2 +R.sub.3 completes 4-6 carbon cycloalkane or spiro fused arene, piperidine or tetrahydropyran;
Ting, et al., in EP 0347698 Al, described a series of heterobicyclic compounds having antiinflammatory activity with formula ##STR5## where A represents a fused 5- or 6-membered heterocyclic aromatic ring containing 1 to 3 heteroatoms in the ring, each heteroatom independently represents O, S, N or NR.sup.6 where R.sup.6 is the group NR.sup.6 is H or C.sub.1 to C.sub.4 alkyl; the double lines represent optional double bond, such that when the bond to X is double, X is O or S; and when the bond to X is a single bond, X is OR.sup.10 where R.sup.10 is alkyl of aralkyl; T.sup.2 and T.sup.3 independently represent S, SO or SO.sub.2 ; m and n independently represent 0 or 1; and R.sup.1 is H, alkyl, aryl, or aralkyl; R.sup.2 and R.sup.3 independently represent H, alkyl, halogen, aryl or aralkyl, etc.